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At least 19 recordsLinked to original sources
PubMed2003

Exhaled breath condensate acidification in acute lung injury.

Lung injury in ventilated lungs may occur due to local or systemic disease and is usually caused by or accompanied by inflammatory processes. Recently, acidification of exhaled breath condensate pH (EBC-pH) has been suggested as marker of inflammation in airway disease. We investigated pH, ammonia, Lactate, pCO2, HCO3-, IL-6 and IL-8 in EBC of 35 ventilated patients (AECC-classification: ARDS: 15, ALI: 12, no lung injury: 8). EBC-pH was decreased in ventilated patients compared to volunteers (5.85 +/- 0.32 vs. 7.46 +/- 0.48; P < 0.0001). NH4+, lactate, HCO3-, pCO2, IL-6 and IL-8 were analyzed in EBC and correlated with EBC-pH. We observed correlations of EBC-pH with markers of local (EBC IL-6: r = -0.71, P < 0.0001, EBC IL-8: r = -0.68, P < 0.0001) but not of systemic inflammation (serum IL-6, serum IL-8) and with indices of severity of lung injury (Murray's Lung Injury Severity Score; r = -0.73, P < 0.0001, paO2/FiO2; r = 0.54, P < 0.001). Among factors potentially contributing to pH of EBC, EBC-lactate and EBC-NH4+ were found to correlate with EBC-pH. Inflammation-induced disturbances of regulatory mechanisms, such as glutaminase systems may result in EBC acidification. EBC-pH is suggested to represent a marker of acute lung injury caused by or accompanied by pulmonary inflammation.

Acute Disease↗
PubMed1997

Pyrrolidine dithiocarbamate attenuates endotoxin-induced acute lung injury.

Lung injury in the acute respiratory distress syndrome (ARDS) is in part due to polymorphonuclear leukocyte (PMN)-mediated oxidative tissue damage. By means of nuclear factor-kappaB (NF-kappaB) activation, oxidants may also induce several genes implicated in the inflammatory response. The dithiocarbamates are antioxidants with potent inhibitory effects on NF-kappaB. We postulated that the pyrrolidine derivative pyrrolidine dithiocarbamate (PDTC) would attenuate lung injury following intratracheal challenge with endotoxin (lipopolysaccharide; LPS) through its effect as an antioxidant and inhibitor of gene activation. Rats were given PDTC (1 mmole/kg) by intraperitoneal injection, followed by intratracheal administration of LPS. The transpulmonary flux of [125I] albumin (permeability index; PI) was used as a measure of lung injury. Northern blot analysis of total lung RNA was performed to assess induction of tumor necrosis factor-alpha (TNF-alpha) and intercellular adhesion molecule-1 (ICAM-1) messenger RNA (mRNA) as markers of NF-kappaB activation. The effect of in vivo treatment with PDTC on LPS-induced NF-kappaB DNA binding activity in macrophage nuclear extracts was evaluated with the electrophoretic mobility shift assay (EMSA). PDTC administration attenuated LPS-induced increases in lung permeability (PI = 0.16 +/- 0.02 for LPS versus 0.06 +/- 0.01 for LPS + PDTC; P < 0.05). TNF-alpha levels and PMN counts in bronchoalveolar lavage fluid (BALF) were unaffected, as were whole-lung TNF-alpha and ICAM-1 mRNA expression. PDTC had no effect on NF-kappaB activation as evaluated with EMSA. PDTC reduced lung lipid peroxidation as assessed by levels of malondialdehyde, without reducing neutrophil oxidant production. We conclude that PDTC attenuates LPS-induced acute lung injury. This effect occurs independently of any effect on NF-kappaB. PDTC reduces oxidant-mediated cellular injury, as demonstrated by a reduction in the accumulation of malondialdehyde. Administration of PDTC may represent a novel approach to limiting neutrophil-mediated oxidant injury.

Animals↗
PubMed2002

Drug-induced lung injury.

Lung injury is an increasing cause of morbidity and mortality in patients treated with cytotoxic and noncytotoxic drugs. Prompt diagnosis is important because early drug-induced lung injury will often regress with the cessation of therapy. Diagnosis requires a high index of suspicion because infection, radiation pneumonitis, and recurrence of the underlying disease can manifest clinically and radiologically in a similar manner. Because the lungs have only a limited number of histopathologic responses to injury, including pulmonary edema/diffuse alveolar damage, NSIP, BOOP, EP, and pulmonary hemorrhage, knowledge of these manifestations and the corresponding radiologic manifestations can often be useful in suggesting a diagnosis of drug-induced lung injury. An understanding of the drugs most commonly associated with lung injury can also facilitate diagnosis.

Anti-Infective Agents↗
PubMed1995

Pre mortem analysis of lung injury and lung function in oxygen toxic rabbits.

OBJECTIVES: To determine whether respiratory system mechanics measurements could detect lung injury in oxygen toxic rabbits before clinical deterioration. To determine whether respiratory system mechanics measurements, using a power analysis, have the statistical power to detect significant reductions in hyperoxic lung injury due to an intervention when compared with traditional post mortem measurements of lung injury, extravascular lung water, and bronchoalveolar lavage protein concentration. DESIGN: Prospective, controlled study. SETTING: Institutional animal laboratories. SUBJECTS: Adult New Zealand white rabbits. INTERVENTIONS: Spontaneously breathing adult New Zealand white rabbits were exposed continuously to either > 95% oxygen or room air. MEASUREMENTS AND MAIN RESULTS: We measured arterial pH, blood gas tensions, and respiratory system mechanics in rabbits twice, both before exposure to > 95% oxygen, and after the rabbits developed symptoms of mild lung dysfunction. After the second set of respiratory system mechanics measurements, we measured extravascular lung water and bronchoalveolar lavage protein concentration in the hyperoxia-exposed rabbits and compared the values with those values obtained in animals that breathed room air only. Our hyperoxia-exposed rabbits developed symptoms of mild respiratory impairment at 69 +/- 2 hrs. In these hyperoxia-exposed rabbits, measurements of static compliance, quasi-static compliance and resistance all changed significantly (p < .05) when compared with baseline measurements. Functional residual capacity and arterial blood gas values did not change significantly. Furthermore, assuming that an intervention reduced hyperoxic lung injury by a given amount, we performed a power analysis and found that the measurement of static compliance had at least equivalent power to detect a reduction in lung injury from an intervention when compared with measurement of extravascular lung water and bronchoalveolar lavage protein concentration. CONCLUSIONS: Measurements of respiratory system mechanics can detect lung injury in hyperoxic rabbits before the onset of severe clinical deterioration or death. Furthermore, measurement of static compliance of the respiratory system is likely to be a powerful tool to detect a reduction in lung injury produced by an intervention.

Airway Resistance↗
PubMed1981

The effect of prostacyclin infusion on endotoxin-induced lung injury.

Lung injury produced by endotoxin is characterized by both pulmonary hypertension and increased pulmonary vascular permeability. Prostacyclin (PGI2) has been found to be a vasodilator and a membrane stabilizer. The purpose of this study was to determine the effectiveness of PGI2 in preventing endotoxin injury. Eight sheep with chronic lung lymph fistula were given both Escherichia coli endotoxin (2 microgram/kg) alone and endotoxin plus an immediate infusion of PGI2 (0.1 to 0.2 microgram/kg/min) for a 5-hour period; the studies were performed 4 days apart. The endotoxin injury was characterized by early severe pulmonary hypertension, with pulmonary artery pressure increasing from 18 +/- 0.6 to 40 +/- 3.1 mm Hg and lung lymph flow (QL) increasing threefold. This was followed in about 3 hours by an increase in permeability characterized by an increasing lymph to plasma protein ratio (0.63 to 0.74) and a threefold increase in QL. In seven of eight animals infused with PGI2 the pulmonary hypertension and alteration in QL in the early and later phases were significantly decreased. In four paired studies, prostaglandins PGE, PGF2 alpha, and PGI2 as 6-keto PGF1 alpha were measured in lymph and plasma. PGF2 alpha and PGI2 were significantly increased in lung lymph during the early hypertensive phase immediately after endotoxin injection, but returned to baseline during the later phase. In the PGI2 infusion studies, PGF2 alpha showed the same pattern of response, but PGI2 was increased to much higher levels in lymph and plasma, as compared to values of endotoxin alone. The higher plasma values corresponded with less severe lung injury. The one animal not protected by PGI2 had the lowest plasma PGI2 level. We therefore found PGI2 to protect the lung against injury from endotoxin.

Animals↗
PubMed2000

Pulmonary aspiration and lung injury.

Lung injury after aspiration, although very rare, is a feared and potentially devastating sequela after anaesthesia. This paper summarizes the most recent studies in aspiration lung injury focusing on its clinical epidemiology, new insights in its pathophysiology and innovative concepts in its prevention and therapy.

Journal Article↗
PubMed1998

Increased endothelial cell expression of platelet-endothelial cell adhesion molecule-1 during hyperoxic lung injury.

Lung injury is a frequent consequence of oxygen (O2) therapy administered to newborns and adults with respiratory distress. Acute exposure to hyperoxia results in a well-described pathophysiologic response in the lungs. Because inflammation is an important component of pulmonary O2 toxicity, we have an interest in identifying the inflammatory mediators that increase during hyperoxia. Platelet-endothelial cell adhesion molecule-1 (PECAM-1), a member of the immunoglobulin superfamily that is expressed at the junctions between endothelial cells, is essential to the transendothelial migration of leukocytes. We hypothesized that increased expression of PECAM-1 occurs in pulmonary endothelial cells during hyperoxic lung injury. Adult mice were exposed to 100% O2 for up to 96 h. We analyzed PECAM-1 expression by RNA blot hybridization, in situ hybridization, and immunohistochemistry. A increase in PECAM-1 mRNA was seen as soon as 2 d of hyperoxia relative to unexposed control mice. PECAM-1 mRNA and protein were found in endothelial cells of both large and small arteries. The expression of PECAM-1 in capillary vessels was further confirmed using in situ hybridization at the electron microscope level. This increase in PECAM-1 expression coincided with the appearance of leukocytes in lung tissue. These observations suggest that PECAM-1 expression is a relatively early step in the inflammation cascade, and intervention at this phase may be critical to the prevention of further damage.

Alternative Splicing↗
PubMed2005

In vivo gene silencing (with siRNA) of pulmonary expression of MIP-2 versus KC results in divergent effects on hemorrhage-induced, neutrophil-mediated septic acute lung injury.

Lung injury in trauma patients exposed to a secondary infectious/septic challenge contributes to the high morbidity/mortality observed in this population. Associated pathology involves a dys-regulation of immune function, specifically, sequestration of activated polymorphonuclear neutrophils (PMN) in the lungs. The targeting of PMN is thought to involve the release of chemokines from cells within the local environment, creating a concentration gradient along which PMN migrate to the focus of inflammation. Keratinocyte-derived chemokine (KC) and macrophage-inflammatory protein-2 (MIP-2) are murine neutrophil chemokines identified as playing significant but potentially divergent roles in the pathogenesis of acute lung injury (ALI). In the current study, we examined the contribution of local pulmonary cells to the production of KC and MIP-2 and the pathogenesis of ALI. We hypothesized that local silencing of KC or MIP-2, via the local administration of small interference RNA (siRNA) against KC or MIP-2, following traumatic shock/hemorrhage (Hem), would suppress signaling for PMN influx to the lung, thereby reducing ALI associated with a secondary septic challenge (cecal ligation and puncture). Assessment of siRNA local gene silencing was done in green fluorescent protein (GFP)-transgenic, overexpressing mice. A marked suppression of GFP expression was observed in the lung 24 h following intratracheal (i.t.) instillation of GFP siRNA, which was not observed in the liver. To test our hypothesis, siRNA against KC or MIP-2 (75 ug/C3H/Hen mouse) was instilled (i.t.) 2 h post-Hem (35 mm Hg for 90 min, 4x LRS Rx.). Twenty-four hours after, mice were subjected to septic challenge and then killed 24 h later. i.t. MIP-2 siRNA significantly (P < 0.05, ANOVA-Tukey's test, n = 5-6/group) reduced tissue and plasma interleukin (IL)-6, tissue MIP-2 (enzyme-linked immunosorbent assay), as well as neutrophil influx [myeloperoxidase (MPO) activity]. In contrast, KC siRNA treatment reduced plasma KC, tissue KC, and IL-6 but produced no significant reduction in plasma IL-6 or MPO. Neither treatment reduced tissue or plasma levels of tumor necrosis factor alpha compared with vehicle. These data support not only our hypothesis that local pulmonary chemokine production of MIP-2, to a greater extent than KC, contributes to the pathogenesis of PMN-associated ALI following Hem but also the use of siRNA as a potential therapeutic.

Animals↗
PubMed1984

Adult respiratory distress syndrome: mechanisms of lung injury.

Lung injury in the adult respiratory distress syndrome (ARDS) may be mediated through a variety of mechanisms and may involve the interaction of a number of systems involved in the inflammatory reaction--complement, granulocytes, prostaglandins and platelets. Studies in animals, involving the infusion of endotoxin, have produced convincing evidence that these agents can cause pulmonary vascular injury and a syndrome resembling human ARDS. Direct evidence of these pathogenic mechanisms in man is lacking, however, but some suggestive clues have emerged in the last few years that support this general scheme. Secondary lung injury through inappropriate fluid administration, sepsis, oxygen toxicity and barotrauma is potentially avoidable. Improved understanding of the pathophysiology of ARDS and improved hemodynamic monitoring should allow minimising of fluid administration and positive end-expiratory pressure in the management of these patients without dangerous impairment of cardiac output. Such an approach, combined with the avoidance of colloid in the early stages of the disease, and the use of vasoactive agents to support cardiac output if necessary, should minimise edema formation and barotrauma and maximise tissue oxygenation. Pulmonary sepsis continues to play an important role in ARDS. Patients are frequently infected after the initial pulmonary injury; such patients have a far worse prognosis than those who are not infected. Until ways are established at a cellular level to minimise colonisation of the upper respiratory tract, reliance must be placed on avoidance of cross infection by strict personal hygiene, avoidance of prophylactic antibiotics, and prompt, vigorous treatment of suspected pulmonary infection.

Biomechanical Phenomena↗
PubMed1990

Altered surfactant function and metabolism in rabbits with acute lung injury.

Lung injury was induced in rabbits with N-nitroso-N-methylurethane (NNNMU), and saturated phosphatidylcholine (Sat PC) pool sizes and phospholipid compositions were measured in alveolar wash subfractions isolated by differential centrifugation (large and small surfactant aggregates). Surfactant metabolism also was studied using intravascular and intratracheal radiolabels. Protein permeability, gas exchange, and compliance were significantly abnormal as lung injury progressed. At peak injury, there was a decrease in the large aggregate Sat PC pool size in alveolar wash accompanied by increased uptake of Sat PC from the air space and increased specific activity of both intravascular and intratracheal radiolabels in lamellar bodies. This was followed by a marked rise in the small aggregate pool size in the alveolar wash and increased secretion of Sat PC into the air spaces. Phospholipid compositions, total phospholipid-to-protein ratios, and in vivo functional studies using a preterm ventilated rabbit model were abnormal for both large and small aggregate surfactant fractions from the lung-injured rabbits. These studies characterize quantitative, qualitative, and functional changes of alveolar wash surfactant subfractions in NNNMU-injured lungs.

Animals↗
PubMed1998

G-protein activation and expression in lung injury.

Lung injury and repair are characterized by changes in the phenotypic and functional characteristics of parenchymal cells. It is not known to what extent these changes are regulated by alterations in total G-protein activity or expression of G-protein subfamilies. G-proteins (GTPases) are receptor-associated proteins that act as molecular switches for signal transduction pathways. They are involved in regulating ribosomal protein synthesis, transmembrane signaling of hormones and growth factors, cellular differentiation and proliferation and guiding organelle movement within cells. In this study, we validated, modified and optimized the experimental conditions needed to evaluate GTPase activity in the lung. We also measured changes in GTPase activity and the expression of G-protein subfamilies in lungs undergoing paraquat lung injury. Total GTPase activity as well as the expression of Gi, Gs, and Go subfamilies demonstrated a sharp increase on day 1 after injury, a time previously shown to coincide with rapid cellular proliferation and increased protein synthesis. In contrast to the other subfamilies, expression of the alpha subunit of the Gs subfamily was more intense and sustained during the repair phase (day 14). These findings implicate G-proteins in general, and the Gs subfamily, in particular, in regulating cellular function during lung repair.

Analysis of Variance↗
PubMed1999

Alveolar epithelial fluid transport capacity in reperfusion lung injury after lung transplantation.

Reperfusion lung injury is an important cause of morbidity and mortality after orthotopic lung transplantation. The purpose of this study was to investigate the function of the alveolar epithelium in the setting of reperfusion lung injury. Simultaneous samples of pulmonary edema fluid and plasma were collected from eight patients with severe post-transplantation reperfusion edema. The edema fluid to plasma protein ratio was measured, an indicator of alveolar-capillary barrier permeability. The initial edema fluid to plasma protein ratio was > 0.75 in six of eight patients, confirming the presence of increased permeability of the alveolar-capillary barrier. Graft ischemic time was positively correlated with the degree of permeability (r = 0.77, p < 0.05). In four of six patients with serial samples, there was a high rate of alveolar fluid clearance (19 +/- 9%/h, mean +/- SD). Alveolar fluid clearance was calculated from serial samples in six patients. Intact alveolar fluid clearance correlated with less histologic injury, rapid resolution of hypoxemia, and more rapid resolution of radiographic infiltrates. The two patients with no net alveolar fluid clearance had persistent hypoxemia and more severe histologic injury. This study provides the first direct evidence that increased permeability to protein is the usual cause of reperfusion edema after lung transplantation, with longer ischemic times associated with greater permeability to protein in the transplanted lung. The high rates of alveolar fluid clearance indicate that the fluid transport capacity of the alveolar epithelium may be well preserved in the allograft despite reperfusion lung injury. The ability to reabsorb fluid from the alveolar space was a marker of less severe reperfusion injury, whereas the degree of alveolar-capillary barrier permeability to protein was not. Measurement of alveolar fluid clearance may be useful to assess the severity of reperfusion lung injury and to predict outcome when pulmonary edema develops after lung transplantation.

Adult↗
PubMed2006

Retrospective analysis of steroid therapy for radiation-induced lung injury in lung cancer patients.

PURPOSE: To disclose characteristics of lung cancer patients developing radiation-induced lung injury treated with or without corticosteroid therapy. METHODS AND MATERIALS: Radiographic changes, symptoms, history of corticosteroid prescription, and clinical course after 50-70 Gy of thoracic radiotherapy were retrospectively evaluated in 385 lung cancer patients. RESULTS: Radiation-induced lung injury was stable without corticosteroid in 307 patients (Group 1), stable with corticosteroid in 64 patients (Group 2), and progressive to death despite corticosteroid in 14 patients (Group 3). Fever and dyspnea were noted in 11%, 50% and 86% (p<0.001), and in 13%, 44% and 57% (p<0.001) patients in Groups 1-3, respectively. Median weeks between the end of radiotherapy and the first radiographic change were 9.9, 6.7 and 2.4 for Groups 1-3, respectively (p<0.001). The initial prednisolone equivalent dose was 30-40 mg daily in 52 (67%) patients. A total of 16 (4.2%) patients died of radiation pneumonitis or steroid complication with a median survival of 45 (range, 8-107) days. CONCLUSION: Development of fever and dyspnea, and short interval between the end of radiotherapy and the first radiographic change were associated with fatal radiation-induced lung injury. Prednisolone 30-40 mg daily was selected for the treatment in many patients.

Adrenal Cortex Hormones↗
PubMed1995

Lung preservation and lung injury.

Lung preservation and its attendant ischemia-reperfusion injury is a complex phenomenon that begins with lung injury that may be present in the donor before any preservation intervention. Acute preservation interventions in common use include single-flush perfusion and donor core-cooling on cardiopulmonary bypass. From this moment forward the ischemia injury begins, and increases during the phase of organ storage. The lung continues to metabolize glucose even at these low temperatures, and future improvements may well lie in recognizing this requirement. With reperfusion, another phase of lung injury begins as the ischemic lung is overloaded with oxygen and oxygen free radicals are generated. Research efforts have focused on minimizing the effect of free-radicals at various steps along their formation and diminishing their interaction with cell membranes.

Animals↗
PubMed1994

Pathways of fibrin turnover in lavage of premature baboons with hyperoxic lung injury.

Lung injury induced by 100% O2 over 6 days is characterized by markedly less alveolar fibrin and rare hyaline membranes in premature versus adult baboons. To determine the mechanism(s) underlying alveolar fibrin deposition in the evolution of hyaline membrane disease (HMD) through diffuse alveolar damage (DAD) and bronchopulmonary dysplasia (BPD), we measured procoagulant and fibrinolytic activities in lung lavage of premature baboons with HMD, those treated with 100% O2 for 6 days (DAD) or for 7 days followed by 14 days 80% O2 (BPD). Lavage procoagulant activity, mainly due to tissue factor associated with Factor VII, was increased by hyperoxia. Plasminogen-dependent fibrinolytic activity, due to both tissue plasminogen activator and urokinase, was stable or increased after hyperoxia. Plasminogen activator inhibitor 1 (PAI-1) was detectable in lavage of animals with HMD but not those with evolving DAD or BPD. Antiplasmin activity was stable or decreased. Although plasminogen was undetectable in lavage, D-dimer was increased in lavage of the groups exposed to hyperoxia versus HMD. The defect in plasminogen activator activity in lavage fluids of adult baboons with DAD induced by O2 does not occur in premature baboons with HMD, evolving DAD, or BPD. Expression of fibrinolytic activity in the lower respiratory tract of premature baboons is dependent on local access to plasminogen, which is present in relatively low concentrations in plasma of these animals.

Age Factors↗
PubMed2002

Role of DNA repair in particle- and fiber-induced lung injury.

Lung injury after particle exposure is associated with the generation of reactive oxygen species (ROS), leading to increased levels of oxidative DNA damage. Furthermore, both stable and unstable DNA lesions may arise after metabolization of polycyclic aromatic hydrocarbons (PAH) frequently bound to particles. Oxidative DNA damage is predominantly removed by base excision repair (BER), which is usually comparatively fast and efficient. Nevertheless, even without exogenous exposure a measurable steady-state level of oxidative DNA lesions exists due to oxygen metabolism, and repair capacities may be exceeded upon particle exposure. Stable DNA adducts induced by PAHs are eliminated by nucleotide excision repair (NER), which is unequally distributed in the genome and incomplete in transcriptionally inactive DNA regions. Thus, even low adduct levels due to environmental exposure lead to persistent lesions in the human lung. Other factors that need to be considered are potential repair inhibitions by associated metal compounds and interindividual differences in repair capacities. Taken together, the extent of DNA repair is an important determinant in particle-induced genotoxicity and carcinogenicity.

Carcinogens↗
PubMed1994

Effect of prostacyclin PGI2 on cardiopulmonary bypass-induced lung injury.

Lung injury produced by cardiopulmonary bypass (CPB) is clinically characterized as postperfusion pulmonary dysfunction syndrome. The roles of humoral factors, altered perfusion modes and the occurrence of diffuse microembolism have been subjects of a number of studies. This paper presents the effectiveness of a platelet inhibiting drug, PGI2 in preventing occlusive microaggregates in the pulmonary circulation. In a series of experimental dog studies using a PGI2 dosage protocol of 10 ng/kg/minute for 30 minutes prior to the onset of CPB followed by 20 mg/kg/minute during CPB, the following effects have been observed: 1) Preservation of platelet numbers during CPB (p < 0.01 versus controls; n = 16). 2) Significant reduction in platelet aggregation during CPB (p < 0.01; n = 16). 3) Insignificant hypotensive effect at normal levels of peripheral vascular resistance (n = 16). 4) Occlusive fibrin, leucocytes and small platelet-based microaggregates obstructing pulmonary arterioles in six of the seven control dogs but in none of the dogs receiving PGI2 infusion. 5) No evidence of perivascular or intra-alveolar oedema, interstitial inflammatory cell infiltrates or haemorrhage was seen in either group of dogs. The controversy existing in relation to the possible therapeutic role of PGI2 and, in particular, its ability to prevent occlusive microaggregates in the arterioles and capillaries of vital organs should encourage further clinical studies of PGI2 and its derivatives during cardiac surgery.

Animals↗